Browsing by Author "Hauser, Michael A."

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    Epistatic gene-based interaction analyses for glaucoma in eMERGE and NEIGHBOR Consortium
    (Public Library of Science, 2016) Verma, Shefali Setia; Bailey, Jessica N. Cooke; Lucas, Anastasia; Bradford, Yuki; Linneman, James G.; Hauser, Michael A.; Pasquale, Louis R.; Peissig, Peggy L.; Brilliant, Murray H.; McCarty, Catherine A.; Haines, Jonathan L.; Wiggs, Janey L.; Vrabec, Tamara R.; Tromp, Gerard; Ritchie, Marylyn D.; eMERGE Network; NEIGHBOR Consortium
    Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies.
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    International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci
    (Nature Research (part of Springer Nature), 2019) Nievergelt, Caroline M.; Maihofer, Adam X.; Klengel, Torsten; Atkinson, Elizabeth G.; Chen, Chia-Yen; Choi, Karmel W.; Coleman, Jonathan R. I.; Dalvie, Shareefa; Duncan, Laramie E.; Gelernter, Joel; Levey, Daniel F.; Logue, Mark W.; Polimanti, Renato; Provost, Allison C.; Ratanatharathorn, Andrew; Stein, Murray B.; Torres, Katy; Aiello, Allison E.; Almli, Lynn M.; Amstadter, Ananda B.; Andersen, Soren B.; Andreassen, Ole A.; Arbisi, Paul A.; Ashley-Koch, Allison E.; Austin, S. Bryn; Avdibegovic, Esmina; Babic, Dragan; Bækvad-Hansen, Marie; Baker, Dewleen G.; Beckham, Jean C.; Bierut, Laura J.; Bisson, Jonathan I.; Boks, Marco P.; Bolger, Elizabeth A.; Borglum, Anders D.; Bradley, Bekh; Brashear, Megan; Breen, Gerome; Bryant, Richard A.; Bustamante, Angela C.; Bybjerg-Grauholm, Jonas; Calabrese, Joseph R.; Caldas-de-Almeida, Jose M.; Dale, Anders M.; Daly, Mark J.; Daskalakis, Nikolaos P.; Deckert, Jurgen; Delahanty, Douglas L.; Dennis, Michelle F.; Disner, Seth G.; Domschke, Katharina; Dzubur-Kulenovic, Alma; Erbes, Christopher R.; Evans, Alexandra; Farrer, Lindsay A.; Feeny, Norah C.; Flory, Janine D.; Forbes, David; Franz, Carol E.; Galea, Sandro; Garrett, Melanie E.; Gelaye, Bizu; Geuze, Elbert; Gillespie, Charles; Uka, Aferdita Goci; Goci, Aferdita; Guffanti, Guia; Hammamieh, Rasha; Harnal, Supriya; Hauser, Michael A.; Heath, Andrew C.; Hemmings, Sian M. J.; Hougaard, David Michael; Jakovljevic, Miro; Jett, Marti; Johnson, Eric Otto; Jones, Ian; Jovanovic, Tanja; Qin, Xue-Jun; Junglen, Angela G.; Karstoft, Karen-Inge; Kaufman, Milissa L.; Kessler, Ronald C.; Khan, Alaptagin; Kimbre, Nathan A.; King, Anthony P.; Koen, Nastassja; Kranzler, Henry R.; Kremen, William S.; Lawford, Bruce R.; Lebois, Lauren A. M.; Lewis, Catrin E.; Linnstaedt, Sarah D.; Lori, Adriana; Lugonja, Bozo; Luykx, Jurjen J.; Lyons, Michael J.; Maples-Keller, Jessica; Marmar, Charles; Martin, Alicia R.; Maurer, Douglas; Mavissakalian, Matig R.; McFarlane, Alexander; McGlinchey, Regina E.; McLaughlin, Katie A.; McLean, Samuel A.; McLeay, Sarah; Mehta, Divya; Milberg, William P.; Miller, Mark W.; Morey, Rajendra A.; Morris, Charles Phillip; Mors, Ole; Mortensen, Preben B.; Neale, Benjamin M.; Nelson, Elliot C.; Nordentoft, Merete; Norman, Sonya B.; O'Donnell, Meaghan; Orcutt, Holly K.; Panizzon, Matthew S.; Peters, Edward S.; Peterson, Alan L.; Peverill, Matthew; Pietrzak, Robert H.; Polusny, Melissa A.; Rice, John P.; Ripke, Stephan; Risbrough, Victoria B.; Roberts, Andrea L.; Rothbaum, Alex O.; Rothbaum, Barbara O.; Roy-Byrne, Peter; Ruggiero, Ken; Rung, Ariane; Rutten, Bart P. F.; Saccone, Nancy L.; Sanchez, Sixto E.; Schijven, Dick; Seedat, Soraya, 1966-; Seligowski, Antonia V.; Seng, Julia S.; Sheerin, Christina M.; Smith, Alicia K.; Smoller, Jordan W.; Sponheim, Scott R.; Stein, Dan J.; Stevens, Jennifer S.; Sumner, Jennifer A.; Teicher, Martin H.; Thompson, Wesley K.; Trapido, Edward; Uddin, Monica; Ursano, Robert J.; Van Den Heuvel, Leigh Luella; Van Hooff, Miranda; Vermetten, Eric; Vinkers, Christiaan H.; Voisey, Joanne; Wang, Yunpeng; Wang, Zhewu; Werge, Thomas; Williams, Michelle A.; Williamson, Douglas E.; Winternitz, Sherry; Wolf, Christiane; Wolf, Erika J.; Wolff, Jonathan D.; Yehuda, Rachel; Young, Ross McD; Young, Keith A.; Zhao, Hongyu; Zoellner, Lori A.; Liberzon, Israel; Ressler, Kerry J.; Haas, Magali; Koenen, Karestan C.
    The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.